PROJECT SUMMARY Since 2005, therapeutic hypothermia/targeted temperature management (TH/TTM) has been recommended for comatose patients recovering from out-of-hospital cardiac arrest (OHCA) due to a shockable first documented rhythm in an attempt to attenuate reperfusion injury, preserve neurological function, and improve long-term survival. After more than a decade of availability, the appropriate application of TH/TTM after non- shockable OHCA, to maximize neurologically intact survival and avoid harm, has not yet been defined. Our research is aimed at filling this knowledge gap. Our central hypothesis, based on our preliminary data, is that TH/TTM outcomes, compared with normal treatment (NT), will vary by rhythm classification. The scientific premise for performing this study is that, without any convincing evidence, TH/TTM has been extrapolated beyond its proven indication to a group of patients in whom, for some, it may actually cause harm. From the Cardiac Arrest Registry to Enhance Survival (CARES) dataset, we will compare neurological status at hospital discharge between two treatment groups (TH/TTM and NT) to determine if the effect of TH/TTM is modified by three presenting rhythm categories ? initially shockable (IS), pulseless electrical activity (PEA), and asystole. We will also compare neurological status at hospital discharge between two treatment groups (TH/TTM and NT) to determine if the effect of TH/TTM in the group with first recorded rhythm of PEA or asystole is modified by conversion to a shockable rhythm during attempted resuscitation (converted shockable [CS] vs. never shockable [NS] rhythms). This research is significant because it will generate the largest, most robust analysis of TH/TTM in non-shockable OHCA event survivors ever reported and innovative in that we seek to alter current research and clinical practice paradigms by challenging the conceptual framework that all non-shockable OHCA patients (PEA [CS and NS] and asystole [CS and NS]) should be grouped together when evaluating and applying TH/TTM as a neuroprotectant. The results generated from this study are expected to more clearly define the appropriate use of TH/TTM in patients recovering from OHCA due to an initially non-shockable rhythm, and thereby advance the NHLBI mission to enhance the health of individuals so that they can live longer and more fulfilling lives.